1. Field of the Invention
This invention relates to solid dosage forms comprising an extended release formulation of calcium salts and to methods for making and using the formulation.
2. Description of Related Art
Calcium is an important human dietary component required for bone formation and maintenance, as well as for many other metabolic functions including functions of the heart, muscles, and nervous system. Calcium from ordinary dietary sources, however, can be insufficient to assure that adequate calcium levels are available in the body to maintain these functions.
To combat this insufficiency, calcium compounds have long been used in the art in various forms, either alone or as ingredients in blends of nutritional supplements. These nutritional supplements include liquids, such as Ensure® brand liquid supplements, and solid dosage forms, such at tablets or capsules. These solid dosage forms may comprise only a calcium supplement, as found in some Citracal® brand calcium supplements or as one ingredient in a combination of supplements, such as in One-A-Day® brand multivitamins.
Calcium supplements have proven beneficial for many different age groups. Children can benefit from having calcium levels sufficient to facilitate bone growth, adults can benefit from calcium levels sufficient to maintain bone health, and seniors can benefit from calcium levels sufficient to minimize bone loss related to osteoporosis. Nutritional supplements containing calcium have even been described for cats (U.S. Pat. No. 7,368,481 to Rapisarda, issued May 6, 2008).
Osteoporosis can be made worse in seniors by an impaired production of vitamin D, which normally stimulates calcium absorption. As a result, calcium is not absorbed as efficiently from the intestines in some seniors. Metabolic processes that require calcium can then draw that calcium from bones, causing a loss in bone density (as described in U.S. Pat. No. 4,772,467 to Pak, issued Sep. 20, 1988). An increased level of calcium in the intestines increases the amount of calcium absorbed, which can help reduce or prevent the loss in bone density. Magnesium has also been proposed as an ingredient that can have beneficial effects if administered in conjunction with calcium.
One difficulty encountered with both solid and liquid forms of calcium supplements lies in the size of the dose. Some authorities have recommended daily levels of calcium as high as 1,000 to 1,500 mg/day. In addition to the calcium ion active ingredient, tablets or liquid suspensions or solutions may also contain an anion species for the calcium ions and various tablet ingredients such as fillers, excipients, lubricating agents, disintegrants, and other ingredients that are well-known in the art of making tablets. Solutions and suspensions also require a carrier fluid and may also include anti-foaming agents, preservatives, stabilizers, and other materials well known in the art of preparing medicinal solutions or suspensions. If a nutritional supplement is to provide that level of calcium, the amount of liquid or the size of the tablet or tablets can be daunting for a person to take in a single dose.
Another problem with large dosage levels of calcium lies in the limits of absorption of calcium by the body and the excretion pathways for calcium. The body can only absorb a limited amount of calcium at a time. Very high levels of available calcium can affect the ability of the stomach or intestine to absorb the calcium. When a large dose of calcium is administered all at once, much of the calcium cannot be absorbed at all. Likewise, the kidneys, which separate excess ions from the blood, tend to separate calcium ions from the blood more quickly when calcium blood levels are high. Once absorbed, the calcium can only be used by the body at a limited rate over the course of the day. Bone formation and maintenance, heart, muscle, and nervous system function and many other metabolic functions that require calcium do not occur at constant rates throughout the day or only in the morning. A single dose of calcium taken in the morning, for example, may not maintain the appropriate levels of calcium in the body throughout the day. Thus, much of the calcium that is administered in a large single dose may either not be absorbed or, if absorbed, may be removed by the kidneys before the body may put it to productive use.
The most direct approach to overcome the inability of the body to put large doses of calcium to use all at once is to administer multiple doses of calcium over the course of a day. Many over-the-counter supplements follow this approach. Caltrate® 600 supplement, for example, advises taking one 600 mg tablet twice daily with food, for a daily dose of 1,200 mg of calcium. One drawback of multiple daily administrations is compliance with the regimen. Particularly with over-the-counter supplements, consumers often forget to take a second or third dose.
Another approach is to employ extended release technology to regulate or delay absorption of the calcium supplement dose. Extended release technology includes delayed release technology and sustained release technologies, including controlled release technology and prolonged release technology.
Delayed release technologies incorporate separate amounts of an active ingredient dose into separate parts of a delivery system. The separate parts of the delivery system are designed to make their portion of the dose available at different times. An example of a delayed release technology would be a multi-layer tablet having separate film coats over each layer. As the tablet moves through the digestive tract, successive layers containing the active ingredient become available for dissolution and use. A graph showing the concentration of the active ingredient in the blood stream over time would be expected to show a series of spikes as each successive layer dissolves.
Sustained release technology uses slow release of active ingredients from a monolithic dosage form. A graph of the concentration of the active ingredient in the blood stream over time would be expected to be a smooth curve. The difference between controlled release technology and delayed release technology is that the concentration of the active ingredient must remain at or about a predefined level in the blood stream for a defined period of time, but in delayed release technology, the concentration of the active ingredient is not constrained to remain at predetermined level.
Various sustained release calcium formulations have been introduced into the market, but those in need of calcium supplements still require a consistent, reliable, single administration, daily dosage form that provides a full day's supply of calcium over an extended time.